Hyperglycemia is the major risk factor for the development of diabetic microvascular complications. The ADA recommends lowering the A1c in T2DM individuals to levels (i.e. HbA1c <6.0-6.5%) as close to normal as possible while avoiding hypoglycemia. The optimal pharmacologic therapy which achieves this goal never has been determined. We have demonstrated that starting newly diagnosed T2DM individuals on a combination of agents (metformin, pioglitazone, exenatide) which correct known pathophysiologic defects in T2DM (Triple Therapy) produces a greater decrease in HbA1c compared to stepwise addition of metformin, sulfonylurea and insulin (Conventional Therapy) and that the decrease in HbA1c was maintained for 36 months of follow-up. Subjects receiving Conventional Therapy experienced significant weight gain (3.7 kg) and a higher rate (7.4-fold increase) of hypoglycemic events compared to subjects receiving Triple Therapy who lost 3.1 kg of body weight. Moreover, Triple Therapy produced profound increases in insulin sensitivity and beta cell function compared to Conventional Therapy. In this grant, we propose to continue to follow-all currently active subjects for an additional 36 months to obtain information about the long term efficacy, durability, safety, and mechanism of action of Triple Therapy compared to Conventional Therapy.